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Anticataleptic properties of alpha2 adrenergic antagonists in the crossed leg position and bar tests: differential mediation by 5-HT1A receptor activation.

Kleven MS, Assié MB, Cosi C, Barret-Grévoz C, Newman-Tancredi A.
Psychopharmacology (Berl). 2005 Feb;177(4):373-80. Epub 2004 Sep 24.

RATIONALE: Recent studies suggest that alpha2 adrenoceptor blockade may improve the antipsychotic-like effects of neuroleptics and attenuate dopamine D2 receptor antagonist-induced catalepsy. However, several alpha2 adrenergic antagonists also display serotonin 5-HT1A receptor agonist activity, which may contribute to anticataleptic actions. OBJECTIVES: In this study, we examined a series of alpha2 adrenergic antagonists to determine the role of activity at serotonin 5-HT1A receptors in their anticataleptic effects. METHODS: Catalepsy in rats induced by the antipsychotic haloperidol (2.5 mg/kg, SC) was measured using the cross-legged position (CLP) and bar tests. The compounds examined in this study, in decreasing rank order of alpha2 adrenergic versus 5-HT1A receptor selectivity, were atipamezole, methoxy-idazoxan (RX821002), efaroxan, idazoxan, and yohimbine. Antagonism studies were conducted using the selective 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide dihydrochloride (WAY100635). RESULTS: Idazoxan, efaroxan, and yohimbine significantly attenuated the cataleptic effects of haloperidol (2.5 mg/kg, SC) in the CLP test and the actions of their highest doses were significantly blocked by pre-treatment with WAY100635 (0.63 mg/kg, SC). In contrast to the other compounds, methoxy-idazoxan was ineffective in the CLP test. Atipamezole exhibited anticataleptic effects in the bar and CLP tests which were not blocked by WAY100635. Similarly, the anticataleptic effects of methoxy-idazoxan and idazoxan in the bar test were not blocked by WAY100635. CONCLUSIONS: Serotonin 5-HT1A receptors play a prominent role in anticataleptic effects of certain alpha2 adrenergic antagonists in the CLP test, whereas alpha2-adrenergic mechanisms are likely to be primarily responsible for the anticataleptic effects of these ligands in the bar test.